TY - JOUR
T1 - Targeting Src in mucinous ovarian carcinoma
AU - Matsuo, Koji
AU - Nishimura, Masato
AU - Bottsford-Miller, Justin N.
AU - Huang, Jie
AU - Komurov, Kakajan
AU - Armaiz-Pena, Guillermo N.
AU - Shahzad, Mian M.K.
AU - Stone, Rebecca L.
AU - Roh, Ju Won
AU - Sanguino, Angela M.
AU - Lu, Chunhua
AU - Im, Dwight D.
AU - Rosenshien, Neil B.
AU - Sakakibara, Atsuko
AU - Nagano, Tadayoshi
AU - Yamasaki, Masato
AU - Enomoto, Takayuki
AU - Kimura, Tadashi
AU - Ram, Prahlad T.
AU - Schmeler, Kathleen M.
AU - Gallick, Gary E.
AU - Wong, Kwong K.
AU - Frumovitz, Michael
AU - Sood, Anil K.
PY - 2011/8/15
Y1 - 2011/8/15
N2 - Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib andoxaliplatinmaybeanattractiveapproachforthis disease.
AB - Purpose: Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma. Experimental Design: A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2). Results: Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model. Conclusions: Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib andoxaliplatinmaybeanattractiveapproachforthis disease.
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U2 - 10.1158/1078-0432.CCR-10-3176
DO - 10.1158/1078-0432.CCR-10-3176
M3 - Article
C2 - 21737505
AN - SCOPUS:80051687960
SN - 1078-0432
VL - 17
SP - 5367
EP - 5378
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -